Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2010 Jan 26:10:9.
doi: 10.1186/1471-230X-10-9.

Prostaglandin E2-induced colonic secretion in patients with and without colorectal neoplasia

Nicolai Kaltoft  1 , Maria C Tilotta, Anne-Barbara Witte, Philip S Osbak, Steen S Poulsen, Niels Bindslev, Mark B Hansen
Affiliations

Prostaglandin E2-induced colonic secretion in patients with and without colorectal neoplasia

Nicolai Kaltoft et al. BMC Gastroenterol. .

Abstract

Background: The pathogenesis for colorectal cancer remains unresolved. A growing body of evidence suggests a direct correlation between cyclooxygenase enzyme expression, prostaglandin E2 metabolism and neoplastic development. Thus further understanding of the regulation of epithelial functions by prostaglandin E2 is needed. We hypothesized that patients with colonic neoplasia have altered colonic epithelial ion transport and express functionally different prostanoid receptor levels in this respect.

Methods: Patients referred for colonoscopy were included and grouped into patients with and without colorectal neoplasia. Patients without endoscopic findings of neoplasia served as controls. Biopsy specimens were obtained from normally appearing mucosa in the sigmoid part of colon. Biopsies were mounted in miniaturized modified Ussing air-suction chambers. Indomethacin (10 microM), various stimulators and inhibitors of prostanoid receptors and ion transport were subsequently added to the chamber solutions. Electrogenic ion transport parameters (short circuit current and slope conductance) were recorded. Tissue pathology and tissue damage before and after experiments was assessed by histology.

Results: Baseline short circuit current and slope conductance did not differ between the two groups. Patients with neoplasia were significantly more sensitive to indomethacin with a decrease in short circuit current of 15.1 +/- 2.6 microA x cm(-2) compared to controls, who showed a decrease of 10.5 +/- 2.1 microA x cm(-2) (p = 0.027). Stimulation or inhibition with theophylline, ouabain, bumetanide, forskolin or the EP receptor agonists prostaglandin E2, butaprost, sulprostone and prostaglandin E1 (OH) did not differ significantly between the two groups. Histology was with normal findings in both groups.

Conclusions: Epithelial electrogenic transport is more sensitive to indomethacin in normal colonic mucosa from patients with previous or present colorectal neoplasia compared to colonic mucosa from control patients. Stimulated epithelial electrogenic transport through individual prostanoid subtype receptors EP1, EP2, EP3, and EP4 is not significantly different between neoplasia diseased patients and controls. This indicates that increased indomethacin-sensitive mechanisms in colonic mucosa from neoplasia diseased patients are not related to differences in functional expression of EP receptor subtypes.

PubMed Disclaimer

Figures

Figure 1
Figure 1
The synthesis, control of tissue level and signalling pathways for PGE2 is presented. The control of tissue level of PGE2 is both through synthesis of PGE2 by the COX enzyme in and its export from pro-inflammatory cells as well as by the removal of PGE2 from the intercellular space by prostaglandin transporter, PGT, and the efficiency of catabolism of PGE2 by enzymes such as 15-prostaglandin dehydrogenease. For instance, expression of the COX-2 enzyme is regulated through many pathways of which several are affected in CRC. As examples of this, somatostatin, SS, has a dampening effect on COX-2 expression, while an autocrine pathway through an epidermal growth factor receptor, EGFR, an EP4 receptor, and microRNA stimulation increase the expression and/or activity of the enzyme. Furthermore, the activity in PGE2-signalling pathways may vary with the expression of the PGE2 receptor subtypes, EP1, EP2, EP3 and EP4, which is affected in CRC. Removal of PGE2 from the extracellular compartment around target cells is by diffusion to the blood stream and uptake and degradation in lung, liver and kidney endothelial cells. Different cellular signalling pathways for PGE2 operation are indicated in the target cell. The activity in various short-term and long-term pathways, as indicated in the target cell, is increased with the CRN/CRC conditions and therefore affecting a host of cell responses, including ion secretion. "Various responses" as mentioned in the figure refers to differentiation, proliferation, survival/apoptosis, exocrine secretion, altered immune response, invasiveness/metastasis, angiogenesis. Abbreviations: AA = arachidonic acid, CBR = carbonyl reductase - also involved in degradation of PGE2, COX1/2 = cyclooxygenase isoforms 1 and 2, EGFR = epidermal growth factor receptor, GPCR = G protein-coupled receptors, miRNA = microRNA, MRP4 = multi-drug resistance related polypeptide 4 - example of an ABC export pump, 15-PGDH = 15-prostaglandin dehydrogenase, PGT = prostaglandin transporter, PL = phospholipid, PLA2 = phospholipase A2, RTK = tyrosine kinase receptor pathway, SS = somatostatin, sst3/5 = somatostatin subtype receptor 3 or 5.
Figure 2
Figure 2
Typical traces of the tissue response to inhibition with 10 μM indomethacin.
Figure 3
Figure 3
Theophylline and forskolin-stimulated short circuit current (SCC) in human colon endoscopic biopsies from C-patients and N-patients is presented. Numbers in parenthesis are numbers of biopsy specimens and number of patients. Increases in SCC after stimulation with 400 μM theophylline (C-patients: 29,18), (N-patients: 7,4) and 1 μM forskolin (C-patients: 45,23), (N-patients: 13,7).
Figure 4
Figure 4
EP receptor subtype agonists (PGE2, butaprost, sulprostone, and PGE1-(OH))-stimulated short circuit current (SCC) in human colon endoscopic biopsies from C-patients and N-patients is presented. Numbers in parenthesis are numbers of biopsy specimens and number of patients. Increases in SCC after stimulation with 200 nM PGE2 (C-patients: 8,5), (N-patients: 6,3); 1.5 μM butaprost (C-patients: 12,10), (N-patients: 11,5); 1 μM sulprostone (C-patients: 11,7), (N-patients: 10,6) and 375 nM PGE1-(OH) (C-patients: 7,6), (N-patients: 9,4).
Figure 5
Figure 5
Indomethacin, bumetanide, and ouabain-induced inhibition of short circuit current in human colon biopsies. Inhibition of electrogenic secretion in endoscopic mucosal biopsies from the sigmoid part of colon from C-patients and N-patients. Numbers in parenthesis are numbers of biopsy specimens and numbers of patients. Decreases in short circuit current (SCC) after inhibition with 10 μM indomethacin (C-patients: 43,24), (N-patients: 21,12); 50 μM bumetanide (C-patients: 12,7), (N-patients: 8,5) and 200 nM ouabain (C-patients: 10,7), (N-patients: 8,5). * p < 0.05.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Gupta RA, Dubois RN. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat Rev Cancer. 2001;1:11–21. doi: 10.1038/35094017. - DOI - PubMed
    1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008. CA Cancer J Clin. 2008;58:71–96. doi: 10.3322/CA.2007.0010. - DOI - PubMed
    1. Backlund MG, Mann JR, Holla VR, Buchanan FG, Tai HH, Musiek ES, Milne GL, Katkuri S, DuBois RN. 15-Hydroxyprostaglandin dehydrogenase is down-regulated in colorectal cancer. J Biol Chem. 2005;280:3217–3223. doi: 10.1074/jbc.M411221200. - DOI - PMC - PubMed
    1. Chell S, Kaidi A, Williams AC, Paraskeva C. Mediators of PGE2 synthesis and signalling downstream of COX-2 represent potential targets for the prevention/treatment of colorectal cancer. Biochim Biophys Acta. 2006;1766:104–119. - PubMed
    1. Hilmi I, Goh KL. Chemoprevention of colorectal cancer with nonsteroidal anti-inflammatory drugs. Chin J Dig Dis. 2006;7:1–6. doi: 10.1111/j.1443-9573.2006.00236.x. - DOI - PubMed

Publication types

MeSH terms